Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Lung squamous cell carcinoma (LUSC) exhibits platinum resistance, partly mediated by cancer stem cells (CSCs).
• Integrin β4 (ITGB4) and SOX2 are highly expressed in LUSC, but their specific roles in platinum resistance require elucidation.

Purpose of the Study:

• To investigate the roles of ITGB4 and SOX2 in platinum resistance in LUSC.
• To evaluate the efficacy of Carfilzomib (CFZ) in overcoming platinum resistance by targeting ITGB4 and SOX2.

Main Methods:

• Analysis of ITGB4 and SOX2 expression in LUSC subtypes and patient survival.
• Isolation and treatment of LUSC CSCs with cisplatin, ITGB4/SOX2 knockdown, and CFZ.
• Assessment of epigenetic mechanisms of SOX2 regulation by CFZ.

Main Results:

• High SOX2 and ITGB4 expression in LUSC, with ITGB4 impacting survival differently across subtypes.
• Knockdown of ITGB4 or SOX2 sensitized cisplatin-resistant LUSC CSCs.
• Carfilzomib (CFZ) synergized with cisplatin, inhibiting ITGB4 and SOX2, and suppressing CSC growth.
• CFZ epigenetically inhibited SOX2 expression via reduced histone acetylation and suppressed SOX2-dependent small cell lung cancer growth.

Conclusions:

• ITGB4 and SOX2 are key drivers of platinum resistance in LUSC CSCs.
• CFZ demonstrates a dual role in overcoming platinum resistance by inhibiting ITGB4/SOX2 and epigenetically suppressing SOX2.
• CFZ represents a potential therapeutic strategy for platinum-resistant LUSC and SOX2-driven cancers.